Aims: We are planning to study potential genetic and environmental risk factors for breast cancer in a cohort of sisters of women with breast cancer. The cohort design we propose will allow us to collect data on exposures, including biological exposure measures, before the onset of disease. The Sister Study offers many advantages. Because we are studying sisters of women with breast cancer, we expect: 1) twice as many cancers as would occur in a similarly-sized general cohort; 2) a higher representation of any relevant genes - including those not yet known to be linked to breast cancer; 3) a higher occurrence of exposure to breast cancer risk factors - especially exposures early in life (that they will tend to share with their affected sister); 4) highly motivated participants who will provide high quality data. These features will enhance our statistical power to detect associations. The study is expected to be large enough to investigate many gene-environment interactions of interest after five years of follow-up. Less common genes and rare exposures can be studied with continued follow-up of the cohort. Procedures and techniques: We propose to investigate the role of gene-environment interactions in breast cancer risk by enrolling and following a cohort of 50,000 sisters of breast cancer cases. Such sisters are at increased risk for breast cancer, giving us enhanced statistical power to detect interactions. The cohort will be large enough to have sufficient cases for examination of many gene-environment interactions after 5 years, but could also be followed longer to create a larger resource for future use. We estimate that a cohort of 50,000 sisters aged 30-74 years will provide about 1,500 breast cancer cases over 5 years. A nationwide campaign will be initiated to recruit sisters. Several recruitment strategies will be pilot-tested before full-scale initiation of the study. Recruitment will involve intensive publicity campaigns and also take advantage of the large networks of breast cancer advocates. Volunteers will be screened for eligibility. Those who quality will complete self-administered questionnaires on the Internet or will by interviewed by telephone using the same structured questionnaires. Women with interesting environmental or occupational exposures will be asked to complete more detailed exposure interviews Participants will be required to provide a blood and urine sample to be frozen for later use. Toenail samples will also be collected. Sisters and recently diagnosed probands will be invited to also participate in a parallel case-control study of breast cancer cases and sister controls that will be used to test current hypotheses and to generate hypotheses for future testing in the cohort study. The cohort will be followed actively over time for the development of breast cancer and other diseases. Tumor tissue and medical records will be sought for incident breast cancer cases. Nested case-control or case-cohort analyses will be carried out among sisters who develop cancer and a sample of those who don't, to assess specific gene-environment interactions. Once assembled, the cohort also will provide the structure for assessing gene-environment interactions in risk for other diseases and will provide opportunities for add-on studies such as comparing tumor characteristics and risk factors in affected sister-pairs. Accomplishments: A study protocol has been drafted and is being submitted for outside peer-review. Eligibility criteria have been formalized and a screening questionnaire was developed. A Sister Study questionnaire is being drafted. Strategies for collecting data via the internet have been evaluated. A web-based screening questionnaire has been developed but the technology is not yet sufficiently advanced to allow for a comprehensive web-based questionnaire. Issues of web security have been explored and protocols to assure the safety of data have been developed. Materials for OMB and IRB submission are being prepared. We obtained a website (www.4Sister.org) and a toll-free telephone number (877-4Sister) that will easily be identified with the study. A preliminary webpage has been developed and is now being expanded to allow for web-based data collection and better information exchange. Focus groups were conducted to assess interest in this study and to identify potential barriers to participation. Separate focus groups were held with breast cancer survivors and sisters - including separate groups for Latina, African American, and lesbian women. The findings from the focus groups have been instrumental in guiding study development. It is clear for example, that while women with breast cancer and their sisters will be motivated to participate, extra efforts will be needed to recruit women from special populations. While some sisters seemed to be most concerned about how to prevent the disease for themselves, the majority seemed motivated by the prospect of eliminating the threat of breast cancer for their daughters. Such women appear willing to participate in research directed towards that end. It was also clear that women who have been diagnosed with breast cancer want to be included. In fact, some seemed insulted that they did not qualify. While the focus of the study is still on the disease-free sisters who may later develop breast cancer, a companion study will include women who were recently diagnosed, provided they have a cancer-free sister who also enrolls in the study. This will allow for initial comparisons of pairs of sisters to address current and new questions related to environmental factors and prognosis.